Topical localized isoxazoline formulation

ABSTRACT

This invention provides topical localized formulations comprising an isoxazoline compound and a pharmaceutically or veterinary acceptable liquid carrier vehicle comprising N,N-diethyl-3-methylbenzamide as a solvent and an improved method for controlling, and preventing parasite infestation in animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/996,263 which is the national stage entry under 35 U.S.C. §371 ofPCT/EP2011/073828, filed on Dec. 22, 2011, which claims priority to U.S.Provisional Application No. 61/430,240, filed on Jan. 6, 2011; and EPApplication No. 10197089.5, filed on Dec. 27, 2010. The contents ofPCT/EP2011/073828 and U.S. application Ser. No. 13/996,263 are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention provides topical localized formulations comprising anisoxazoline compound and a pharmaceutically or veterinary acceptableliquid carrier vehicle. This invention also provides for an improvedmethod for controlling, and preventing parasite infestation in animals.

BACKGROUND OF THE INVENTION

A number of pests and parasites can infest or infect domestic animalssuch as cattle, horses, pigs, sheep and also companion animals such ascats and dogs. These pests and parasites are of great nuisance to boththe animals and their owners.

Ectoparasites such as ticks, mites, lice, flies and fleas irritate theanimals and can cause disease, either by themselves, or by carryingvector transmitted pathogens.

New economic methods and compositions for the prevention, treatment andcontrol of parasites in warm-blooded animals are constantly beingsought.

A new family of insecticide isoxazoline compounds has been described invarious patent applications; for example, in US patent application US2007/0066617, and International Patent applications WO 2007/079162, WO2009/002809, WO 2009/024541, WO 2009/003075, WO 2010/070068, WO2010/079077, WO 2011/075591 and WO 2011/124998.

As these isoxazoline compounds have been originally investigated fortheir use in the agricultural area it is necessary to identify specificformulations that allow their veterinary use, i.e. safe administrationto control parasites in animals effectively.

One known and convenient way of administering an ectoparasiticidecompound to an animal is the topical localized administration, e.g. asspot-on or pour-on.

However, prior art formulations and conventional topical localizedectoparasiticide formulations that use suggested solvents forisoxazoline compounds have difficulties applying effective amounts ofisoxazoline compounds with acceptable cosmetic appearance. Particularly,high volumes of conventional topical localized formulations can resultin product run-off and sodden appearances of the fur afteradministration and high concentration formulations can result ininsolubility (crystallization) of the active ingredient, skin irritationas well as undesirable product characteristics, such as poor viscosity,insufficient spreading, poor evaporation and inadequate permeation.

Thus, what is needed in the art, are topical localized formulations ofisoxazoline compounds, which avoid the drawbacks mentioned above.

SUMMARY OF THE INVENTION

The current invention provides topical localized formulations for theadministration of isoxazoline compounds that overcome the drawbacks ofthe prior art. The formulations of the invention deliver effectiveamounts of isoxazoline compounds after topical localized administrationand with acceptable cosmetic appearance.

In one aspect the current invention is directed to a topical localizedformulation for the treatment or prophylaxis of parasite infestation inanimals which comprises an effective amount of at least one isoxazolinecompound of the Formula (I)

whereinR¹=halogen, CF₃, OCF₃, CN,n=integer from 0 to 3, preferably 1, 2 or 3,R²=C₁-C₃-haloalkyl, preferably CF₃ or CF₂Cl,T=5- or 6-membered ring, which is optionally substituted by one or moreradicals Y,Y=methyl, halomethyl, halogen, CN, NO₂, NH₂—C═S, or two adjacentradicals Y form together a chain, especially a three or four memberedchain;Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals;X═CH₂, CH(CH₃), CH(CN), CO, CS,R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃);R⁴=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl,haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl,propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl,methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl,ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl;

Or R³ and R⁴ together form a substituent selected from the groupconsisting of:

and a veterinary acceptable liquid carrier vehicle wherein the liquidcarrier vehicle comprises N,N-diethyl-3-methylbenzamide as a solvent.

In one embodiment the liquid carrier vehicle comprisesN,N-diethyl-3-methylbenzamide as sole solvent. In another embodiment atleast one additional veterinary acceptable co-solvent is present.

In one embodiment the composition comprises additionally an effectiveamount of a macrocyclic lactone compound selected from ivermectin,moxidectin, milbemycin oxime, selamectin, emamectin, latidectin andlepimectin or a salt thereof and/or an insect growth regulator compoundselected from fenoxycarb, lufenuron, diflubenzuron, novaluron,triflumuron, fluazuron, cyromazine, methoprene and pyriproxyfen.

Another aspect of the current invention is a method for treatment orprophylaxis of parasite infestation of an animal comprising spot-on orpour-on administration of a localized topical formulation of claim 1.

These and other embodiments are disclosed or are obvious from andencompassed by the following Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Plasma concentration of Compound A after spot-on administrationof formulations A, U, D, O, F and G to Beagle dogs

FIG. 2: Plasma concentration of Compound A after spot-on administrationof formulations A, V and I to Beagle dogs

FIG. 3: Plasma concentration of Compound A after spot-on administrationof formulations A, N and R to Beagle dogs

FIG. 4: Plasma concentration of Compound A after spot-on administrationof formulation Q to Beagle dogs

FIG. 5: Plasma concentration of Compound A after spot-on administrationof formulations C and H to Beagle dogs

FIG. 6 Plasma concentration of Compound A after spot-on administrationof formulations N and C to Beagle dogs

FIG. 7 Compound A and moxidectin plasma concentration after spot-onadministration of formulation G to Beagle dogs

DETAILED DESCRIPTION OF THE INVENTION

The topical localized formulation according to the invention comprisesan isoxazoline compound of the Formula (I)

whereinR¹=halogen, CF₃, OCF₃, CN,n=integer from 0 to 3, preferably 1, 2 or 3,R²═C₁-C₃-haloalkyl, preferably CF₃ or CF₂Cl,T=5- or 6-membered ring, which is optionally substituted by one or moreradicals Y,Y=methyl, halomethyl, halogen, CN, NO₂, NH₂—C═S, or two adjacentradicals Y form together a chain CH—CH═CH—CH, N—CH═CH—CH, CH—N═CH—CH,CH—CH═N—CH, or CH—CH═CH—N, HC═HC═CH, CH—CH═CH, CH═CH—N, N—CH═CH;Q=X—NR³R⁴ or a 5-membered N-heteroaryl ring, which is optionallysubstituted by one or more radicals Z^(A), Z^(B) Z^(D);X═CH₂, CH(CH₃), CH(CN), CO, CS,R³=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl,methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl,propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl,dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,tetrahydrofuryl, methylaminocarbonylmethyl,(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,haloethylaminocarbonylcyclopropyl,

R⁴=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl,haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl,propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl,methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl,ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl,haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, orhaloethylaminocarbonylethyl; orR³ and R⁴ together form a substituent selected from the group consistingof:

wherein Z^(A)=hydrogen, halogen, cyano, halomethyl (CF₃);and a veterinary acceptable liquid carrier vehicle wherein the liquidcarrier vehicle comprises N,N-diethyl-3-methylbenzamide as a solvent.

In one preferred embodiment in Formula (I) T is selected from

wherein in T-1, T-3 and T-4 the radical Y is hydrogen, halogen, methyl,halomethyl, ethyl, haloethyl.

In an preferred embodiment in Formula (I) Q is selected from

Wherein R³, R⁴, X and Z^(A) are as defined above.

Preferred compounds of Formula (I) are:

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, 5Cl CF₃ CH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂CH₂OCH₃ H T-2 —Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-Cl, 5ClCF₃ CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O)3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃CH₂C(O)NHCH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-73-Cl, 5Cl CF₃ — — T-2 — Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-73-Cl, 5Cl CF₃ — — T-2 — Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CC H T-3 CH₃ Q-1 — C(O) 3-Cl,5Cl CF₃ CH₂C(O)NHCH₂CN H T-3 CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ HT-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O)3-Cl, 4-Cl, CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 4-Cl,CF₃ CH₂C(O)NHCH₂CH₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 4-F, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃H T-3 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃CH₂C(O)NHCH₂CF₃ CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 —C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CH₃H T-21 Q-1 C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-Cl,5-Cl CF₃ CH₂C(O)NHCH₂CH₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂CH₂SCH₃ HT-21 — Q-1 — C(O) 3-Cl, 4-Cl, CF₃ C(O)CH₃ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl,4-Cl, CF₃ C(O)CH(CH₃)₂ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-Cl, CF₃C(O)-cyclo-propyl H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-F, 5-Cl CF₃ C(O)CH₃ HT-22 F Q-1 — CH₂ 3-Cl, 4-Cl, CF₃ C(O)CH₂CH₃ H T-22 F Q-1 — CH₂ 5-Cl3-Cl, 4-F, 5-Cl CF₃ C(O)CH₃ H T-22 Cl Q-1 — CH₂ 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CH₃ HT-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (Z) H T-1 CH₃ Q-1 — C(O) 3-Cl,5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

Especially preferred compounds of Formula (I) are

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, 5Cl CF₃ CH₂CH₃ H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂CH₂OCH₃ H T-2 —Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ HT-2 — Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2— Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2— Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl,5Cl CF₃ CH₂C(O)NHCH₂CC H T-3 CH₃ Q-1 — C(O) 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CNH T-3 CH₃ Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 —C(O) 3-Cl, 4-Cl, CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl,4-F, CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 5-Cl 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ CH₃T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂CH₂SCH₃ H T-21 —Q-1 — C(O) 3-Cl, 4-Cl, CF₃ C(O)CH₃ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-Cl,CF₃ C(O)CH(CH₃)₂ H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-Cl, CF₃C(O)-cyclo-propyl H T-22 F Q-1 — CH₂ 5-Cl 3-Cl, 4-F, CF₃ C(O)CH₃ H T-22F Q-1 — CH₂ 5-Cl 3-Cl, 4-Cl, CF₃ C(O)CH₂CH₃ H T-22 F Q-1 — CH₂ 5-Cl3-Cl, 4-F, CF₃ C(O)CH₃ H T-22 Cl Q-1 — CH₂ 5-Cl 3-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (Z) H T-1 CH₃Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

A more preferred compound has the formula (II),

whereinR^(1a), R^(1b), R^(1c) are independently from each other hydrogen, Cl orCF₃, preferably R^(1a) and R^(1c) are Cl and R^(1b) is hydrogen,T is

wherein Y is methyl, bromine, Cl, F, CN or C(S)NH₂,Q is as described above.

In another preferred embodiment in R³ is H and R⁴ is—CH₂—C(O)—NH—CH₂—CF₃, —CH₂—C(O)—NH—CH₂—CH₃, —CH₂—CH₂—CF₃ or —CH₂—CF₃.

In one embodiment the compound of formula (I) is4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(CAS RN [864731-61-3]).

In another embodiment the compound of formula (I) is(Z)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide(CAS RN [928789-76-8]).

An especially preferred compound is

Especially preferred compounds of Formula (II) are:

(R¹)_(n) R² R³ R⁴ T Y Q Z X 3-Cl, 5Cl CF₃ CH₂CF₃ H T-2 — Q-1 — C(O)3-Cl, SCl CF₃ CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃CH₂C(O)NHCH₂CF₃ H T-2 — Q-1 — C(O) 3-CF₃, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-2— Q-1 — C(O) 3-Cl, 5Cl CF₃ — T-2 — Q-6 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 —Q-7 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 — Q-5 Z^(B)-7 3-Cl, 5Cl CF₃ — — T-2 —Q-2 Z^(D)-1 3-Cl, 5Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-CF₃,5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 4-Cl, 5-Cl CF₃CH₂C(O)NHCH₂CF₃ H T-3 CH₃ Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃H T-3 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O)3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ CH₃ T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃CH₂C(O)NHCH₂CF₃ H T-20 — Q-1 — C(O) 3-CF₃, 5-CF₃ CF₃ CH₂C(O)NHCH₂CF₃ HT-21 — Q-1 — C(O) 3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-21 — Q-1 — C(O)3-Cl, 5-Cl CF₃ CH₂C(O)NHCH₂CF₃ H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1(Z) H T-1 CH₃ Q-1 — C(O) 3-Cl, 5-Cl CF₃ R³-1 (E) H T-1 CH₃ Q-1 — C(O)

Isoxazoline compounds are known in the art and these compounds and theiruse as parasiticide are described, for example, in US patent applicationNo. US 2007/0066617, and International Patent applications WO2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO2010/070068, WO 2010/079077, WO 2011/075591 and WO 2011/124998, thedisclosures of which, as well as the references cited herein, areincorporated by reference. This class of compounds is known to possessexcellent activity against ectoparasites such as ticks and fleas.

The isoxazoline compounds may exist in various isomeric forms. Areference to an isoxazoline compound always includes all possibleisomeric forms of such compound. Unless otherwise stated, a compoundstructure that does not indicate a particular conformation is intendedto encompass compositions of all the possible conformational isomers ofthe compound, as well as compositions comprising fewer than all thepossible conformational isomers. In some embodiments, the compound is achiral compound. In some embodiments, the compound is a non-chiralcompound.

Isoxazoline compounds of formula (I) can be prepared according to one orother of the processes described e.g. in Patent Applications US2007/0066617, WO 2007/079162, WO 2009/002809, WO 2010/070068 and WO2010/079077, 2011/075591 and WO 2011/124998 or any other process comingwithin the competence of a person skilled in the art who is an expert inchemical synthesis. For the chemical preparation of the products of theinvention, a person skilled in the art is regarded as having at hisdisposal, inter alia, the entire contents of “Chemical Abstracts” and ofthe documents which are cited therein.

The formulations according to the invention are effective for longdurations of time in the treatment of ectoparasites of mammals and, inparticular, of fleas and ticks in small mammals such as dogs and cats.Advantageously, the formulations of the invention retain the desiredphysical characteristics over time, without loss of potency of theactive. Further, the formulations of the invention exhibit sufficientviscosity, which allows for the retention of said composition whenadministered topically to an animal's skin or hair.

Furthermore the formulations of the current invention have favorableproduct characteristics i.e. they are stable and are cosmeticallyacceptable.

Cosmetic acceptability includes the (absence of) smell of hair and skin,wetness of the hair and skin of the application site, the overallappearance of the dogs' coat, particularly signs such as dryness, wirylook, brittleness, dullness, hair loss and the appearance of residue ofthe hair in the proximity of the administration site.

Such cosmetic acceptability is very important for products for topicallocalized administration to companion animals like dogs and cats,because the pet owner would not accept long lasting changes in theappearance of the fur of their pet following the administration.

With the formulations according to the current invention it was possibleto identify topical localized formulations that allow the administrationof isoxazoline compounds for a long acting efficacy against ticks andfleas while being cosmetically acceptable.

Topical localized formulations are understood to refer to a ready-to-useformulation in form of a spot-on, pour-on or spray-on formulation. Theexpression spot-on or pour-on method is understood to refer to aready-to-use concentrate intended to be applied topically and locally onthe animal. This sort of formulation is intended to be applied directlyto a relatively small area of the animal, preferably on the animal'sback and breech or at one or several points along the line of the backand breech.

Spot-on administration is a topical localized administration of aconcentrated solution, suspension, microemulsion or emulsion forintermittent application to a spot on the animal, generally between thetwo shoulders in 1, 2, 3, 4, or 5 locations (spots), if more than onespot preferably down the back of the animal. Alternatively the productis administered by administering a line.

The pour-on formulation is typically applied by pouring in one orseveral lines or in a spot-on along the dorsal midline (back) orshoulder of an animal. More typically, the formulation is applied bypouring it along the back of the animal, following the spine. A pour-onformulation is more common for control of parasites in livestockanimals, such as e.g. cattle, pigs, sheep and horses. The pour-onformulations of this invention can be in the form of a liquid, emulsion,foam, paste, aerosol, ointment, salve or gel. Typically, the pour-onformulation is liquid.

The formulation can also be applied to the animal by other conventionalmethods, including wiping an impregnated material over at least a smallarea of the animal, or applying it using a commercially availableapplicator, by means of a syringe, by spraying or by using a spray race.

A pour-on or spot-on formulation generally can advantageously comprisethe isoxazoline compound of formula (I) in a proportion of about 0.01 toabout 70%, of about 1 to about 50%, 10 to 40%, 20 to 35%, 25 to 30%about 20%, 25%, 28%, 30%, 33%, 50%, (percentages as weight byvolume=W/V).

The topical localized formulation allows or facilitates the isoxazolinecompound to penetrate the skin and act on other body parts (e.g., theentire body). Such a pour-on or spot-on formulation can be prepared bydissolving, suspending, or emulsifying the isoxazoline in a suitableveterinarily acceptable carrier.

In one embodiment the topical localized formulation comprises a carriercomprising N,N-diethyl-3-methylbenzamide (DEET, previously calledN,N-diethyl-meta-toluamide or N,N-Diethyl-m-toluamide) as a solesolvent. In one embodiment at least one additional veterinary acceptableco-solvent is present. N,N-diethyl-3-methylbenzamide is a well knownchemical compound which has long been used as an insect repellant.Various syntheses for the preparation thereof are well-known to the art.

A pour-on or spot-on formulation generally can advantageously comprisethe N,N-diethyl-3-methylbenzamide in a proportion of about 1 to about50%, preferably of about 5 to about 37%, 8 to 28%, 10 to 23%, 15 to 20%about 5%, 7%, 9%, 10%, 11%, 14%, 15%, 17%, 18%, 20%, 23%, 28%, 33%, 37%,44% (percentages as weight by volume=W/V).

The co-solvent for the liquid carrier includes pharmaceuticallyacceptable solvents known in the formulation art.

These solvents include, for example, acetone dichloromethane,glycofurol, acetonitrile, n-butyl ether, monomethylacetamide,dipropylene glycol monomethyl ether, diethyl phthalate fatty acidesters, such as the diethyl ester or diisobutyl adipate, water, alkanol,benzyl benzoate, dipropylene glycol monomethyl ether, diethylene glycolmonobutyl ether, silicone, dimethylacetamide,2,2-dimethyl-4-oxy-methylene-1,3-dioxolane. N, N-dimethylalkanamides(e.g. N,N dimethylformamide), limonene, eucalyptol, dimethyl sulfoxide,-alkylpyrrolidones (e.g. N-methylpyrrolidone, 2-pyrrolidone), liquidpolyoxyethylene glycols, methylene glycol, ethylene glycol, propyleneglycol, dipropylene glycol, polypropylene glycol, butyl diglycol,dipropylene glycol, propylene carbonate, butylene carbonate, paraffins(e.g., white mineral oils, normal paraffins, isoparaffins),alkylbenzenes, alkylnaphthalenes, glycerine, glycerol triacetate,sorbitol, triacetin, aromatic hydrocarbons, dearomatized aliphatics,alkylbenzenes, alkylnaphthalenes, ketones such as methyl ethyl ketone,cyclohexanone, 2-heptanone, isophorone and4-hydroxy-4-methyl-2-pentanone, acetates such as ethyl acetate, benzylacetate, isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate,nonyl acetate, tridecyl acetate and isobornyl acetate, other esters suchas alkylated lactate esters, dibasic esters and γ-butyrolactone, andalcohols, which can be linear, branched, saturated or unsaturated, suchas phenyl ethyl alcohol, methanol, ethanol, n-propanol, isopropylalcohol, n-butanol, isobutyl alcohol, n-hexanol, 2-ethylhexanol,n-octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol,lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol,tetrahydrofurfuryl alcohol, diacetone alcohol and benzyl alcohol.

Such solvents also include glycerol esters of saturated and unsaturatedfatty acids (typically C₆-C₂₂), such as plant seed and fruit oils (e.g.oils of olive, castor, linseed, sesame, corn (maize), peanut, sunflower,grapeseed, safflower, cottonseed, soybean, rapeseed, coconut and palmkern and mixtures thereof, e.g. polyethoxylated castor oil. Suchsolvents also include alkylated fatty acids (e.g., methylated,ethylated, butylated) wherein the fatty acids may be obtained byhydrolysis of glycerol esters from plant and animal sources, and can bepurified by distillation.

In one embodiment the solvent is N,N-diethyl-3-methylbenzamide; and theco-solvent is selected from the group consisting of acetone,acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide,dimethylsulfoxide, dimethylformamide, dipropylene glycol n-butyl ether,ethyl alcohol, isopropanol, methanol, phenylethyl alcohol, isopropanol,ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,monomethylaceamide, dipropylene glycol monomethyl ether, liquidpolyoxyethylene glycols, propylene glycol, N-methylpyrrolidone,2-pyrrolidone, limonene, eucalyptol, diethylene glycol monoethyl ether,ethylene glycol, diethyl phthalate, polyethoxylated castor oil, methylethyl ketone, glycofurol, ethyl-L-lactate, and a mixture of at least twoof these co-solvents.

In another embodiment the co-solvent is selected from the groupconsisting of dimethyl sulfoxide, acetone, dimethylacetamide, ethylalcohol, dipropylene glycol monomethyl ether, methylethyl ketone,glycofurol, ethyl-L-lactate, and a mixture of at least two of thesecosolvents.

In one embodiment the liquid carrier vehicle comprisesN,N-diethyl-3-methylbenzamide as solvent and a organic co-solvent isselected from acetone, ethyl-L-lactate, dimethyl sulfoxide,dimethylacetamide and glycofurol.

In another embodiment the organic solvent in the local topicalformulation is N,N-diethyl-3-methylbenzamide and the organic co-solventis a mixture of at least two of acetone, ethyl-L-lactate, dimethylsulfoxide, dimethylacetamide and glycofurol.

The co-solvent can advantageously be present in the compositionaccording to a volume/volume (V/V) ratio with respect toN,N-diethyl-3-methylbenzamide of between about 4/1 and about 1/5.

A pour-on or spot-on formulation generally can advantageously compriseacetone in a proportion of about 0 to about 50%, preferably of about 5to about 35%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, (percentages asvolume by volume=V/V).

A pour-on or spot-on formulation generally can advantageously comprisedimethylacetamide in a proportion of about 0 to about 60%, preferably ofabout 5 to about 50%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50% (percentages as volume by volume=V/V).

A pour-on or spot-on formulation generally can advantageously comprisedimethylsulfoxide in a proportion of about 0 to about 50%, preferably ofabout 5 to about 35%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%,(percentages as volume by volume).

A pour-on or spot-on formulation generally can advantageously compriseN-methylpyrrolidone in a proportion of about 0 to about 50%, preferablyof about 5 to about 35%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%(percentages as volume by volume).

A pour-on or spot-on formulation generally can advantageously comprisemetylethylketone in a proportion of about 0 to about 50%, preferably ofabout 5 to about 40%, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%(percentages as volume by volume).

The topical localized formulation can also include one or moreadditional ingredients. Examples of suitable additional ingredients arepenetration enhancers, spreading agents, stabilizers such asantioxidants/preservatives, adhesion promoters and viscosity modifiers,crystallization inhibitors, UV blockers or absorbers, water scavengersand colorants. Surface active agents, including anionic, cationic,non-ionic and ampholytic surface active agents, can also be included inthese formulations.

In some embodiments, a topical formulation (particularly a pour-on orspot-on formulation) comprises a carrier that promotes the absorption orpenetration of the isoxazoline through the skin into the blood stream,other bodily fluids (lymph), and/or body tissue (fat tissue).Contemplated examples of dermal penetration enhancers include, forexample, dimethylsulfoxide, isopropyl myristate, dipropylene glycolpelargonate, silicone oil, aliphatic esters, triglycerides, and fattyalcohols.

Topical localized formulations also (or alternatively) may comprise, forexample, one or more spreading agents. These substances act as carriersthat assist in distributing an active ingredient over the animalrecipient's coat or skin. They may include, for example, isopropylmyristate, dipropylene glycol pelargonate, silicone oils, fatty acidesters, triglycerides, and/or fatty alcohols.

Various spreading oil/solvent combinations also may be suitable, suchas, for example, oily solutions, alcoholic and isopropanolic solutions(e.g., solutions of 2-octyl dodecanol or oleyl alcohol), solutions ofesters of monocarboxylic acids (e.g., isopropyl myristate, isopropylpalmitate, lauric acid oxalic ester, oleic acid oleyl ester, oleic aciddecyl ester, hexyl laurate, oleyl oleate, decyl oleate, and caproic acidesters of saturated fatty alcohols having a carbon chain of 12 to 18carbons), solutions of esters of dicarboxylic acids (e.g., dibutylphthalate, diisopropyl isophthalate, adipic acid diisopropyl ester, anddi-n-butyl adipate), or solutions of esters of aliphatic acids (e.g.,glycols). When the formulation comprises a spreading agent, it also maybe advantageous to include a dispersant, such as, for example,pyrrolidin-2-one, N-allylpyrrolidin-2-one, acetone, polyethylene glycol,or an ether or ester thereof, propylene glycol, or synthetictriglycerides.

Optionally a crystallization inhibitor can be present selected from thegroup consisting of an anionic surfactant, a cationic surfactant, anon-ionic surfactant, an amine salt, an amphoteric surfactant orpolyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodiumcarboxymethylcellulose, and acrylic derivatives, or a mixture of thesecrystallization inhibitors.

The formulation can also comprise an antioxidizing agent intended toinhibit oxidation in air.

Particularly preferred antioxidizing agents are those conventional inthe art and include, for example, butylated hydroxyanisole, butylatedhydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate,sodium thiosulphate or a mixture of them.

Suitable exemplary polymers (“polymeric agents”) for gelling and/oradhering that may be used in the compositions of the invention include,but are not limited to, colloidal silicone dioxide, ethyl cellulose,methyl cellulose, methacrylic esters copolymers, carboxylated vinylacetate, and polyvinylpropylene (PVP)/Vinyl acetate copolymers,Poloxamer 124, Poloxamer 188, Polybutene, Povidone K17 and Povidone K90.

The additional ingredients discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques.

The topical localized formulation is applied as a low volume of about0.01 to 1 ml per kg, preferably about 0.05 to 0.1 ml per kg, with atotal volume from 0.3 to 100 ml per animal, preferably limited to amaximum of about 50 ml depending on the target species.

For small companion animals such as dogs and cats the volume applied canbe of the order of about 0.3 to about 6 ml, preferably of the order ofabout 0.4 to 2.0 ml per dose, for cats and of the order of about 0.4 toabout 5 ml for dogs, depending on the weight of the animal.

An exemplary composition for topical administration to warm-bloodedanimals typically comprises, on a weight to volume basis, about 1%-50%w/v of an isoxazoline compound of formula I; about 5 to 25% w/v ofN,N-diethyl-3-methylbenzamide; about 5% to 95% v/v of a co-solvent orsolvent mixture, such as DMSO by itself or in combination with about 10to 20% v/v of acetone, and/or about 10 to 20% v/v of a second cosolvent.

An exemplary composition for topical administration to warm-bloodedanimals typically comprises, on a weight to volume basis, about 1%-50%w/v of an isoxazoline compound of formula I; about 5 to 25% w/v ofN,N-diethyl-3-methylbenzamide; about 5% to 95% v/v of a co-solvent orsolvent mixture, such as N-methylpyrrolidone by itself or in combinationwith about 10 to 50% v/v of acetone, and/or about 10 to 20% w/v of acosolvent.

An exemplary composition for topical administration to warm-bloodedanimals typically comprises, on a weight to volume basis, about 1%-50%w/v of an isoxazoline compound of formula I; about 5 to 25% w/v ofN,N-diethyl-3-methylbenzamide; about 5% to 95% v/v of a co-solvent orsolvent mixture, such as DMA by itself or in combination with about 10to 50% v/v of acetone, and/or about 10 to 20% v/v of a cosolvent.

An exemplary composition for topical administration to warm-bloodedanimals typically comprises, on a weight to volume basis, about 1%-50%w/v of an isoxazoline compound of formula I; about 5 to 25% v/v ofN,N-diethyl-3-methylbenzamide; about 5% to 95% v/v of a co-solvent orsolvent mixture, such as DMA by itself or in combination with about 10to 50% v/v of DMSO, and/or about 10 to 20% v/v of a cosolvent.

An exemplary composition for topical administration to warm-bloodedanimals typically comprises, on a weight to volume basis, about 1%-50%w/v of an isoxazoline compound of formula I; about 5 to 25% w/v ofN,N-diethyl-3-methylbenzamide; about 5% to 95% v/v of a co-solvent orsolvent mixture, such as DMSO by itself or in combination with about 10to 50% v/v of Propylene glycol methyl ether, and/or about 10 to 20% v/vof a cosolvent.

An exemplary composition for topical administration to warm-bloodedanimals typically comprises, on a weight to volume basis, about 1%-50%w/v of an isoxazoline compound of formula I; about 5 to 25% w/v ofN,N-diethyl-3-methylbenzamide; about 5% to 95% v/v of a co-solvent orsolvent mixture, such as DMA or DMSO by itself or in combination withabout 10 to 50% v/v of methyl ethyl ketone, and/or about 10 to 20% w/vof a cosolvent.

In one embodiment of the invention the topical localized formulationcomprise at least one isoxazoline compound of formula I and amacrocyclic lactone compound of the avermectin or milbemycin class ofcompounds. Macrocyclic lactone compounds are either natural products orare semi-synthetic derivatives thereof. The structure of at leastcertain macrocyclic lactone compounds are closely related, e.g., bysharing a complex 16-membered macrocyclic lactone ring.

One compound for use within the scope of the present invention isivermectin. Another macrocyclic lactone is moxidectin. Moxidectin, alsoknown as LL-F28249 alpha, is known from U.S. Pat. No. 4,916,154. Anothermacocyclic lactone is selamectin. Selamectin is25-cyclohexyl-25-de(l-methylpropyl)-5-deoxy-22,23-dihydro-5-(hydroxyimino)-avermectinB1 monosaccharide. Another preferred compound is milbemycin, especiallymilbemycin oxime. Milbemycin, or B41, is a substance which is isolatedfrom the fermentation broth of a milbemycin-producing strain ofStreptomyces. The microorganism, the fermentation conditions and theisolation procedures are described in U.S. Pat. Nos. 3,950,360 and3,984,564.

Emamectin (4″-deoxy-4″-epi-methylaminoavermectin B1), which can beprepared as described in U.S. Pat. Nos. 5,288,710 and 5,399,717, is amixture of two homologues, 4″-deoxy-4″-epi-methylaminoavermectin Bla and4″-deoxy-4″-epi-methylaminoavermectin B1. Preferably, a salt ofemamectin is used. Eprinomectin is chemically known as4″-epi-acetylamino-4″-deoxy-avermectin B1.

For Latidectin, information can be found at “InternationalNonproprietary Names for Pharmaceutical Substances (INN)”. World HealthOrganization (WHO) Drug Information, vol. 17, no. 4, page 278-279,(2003).

Lepimectin is(6R,13R,25R)-5-O-demethyl-28-deoxy-6,28-epoxy-13-[(Z)-[(methoxyimino)phenylacetyl]oxy]-25-methylmilbemycinB mixture with(6R,13R,25R)-5-O-demethyl-28-deoxy-6,28-epoxy-25-ethyl-13-[(Z)-[(methoxyimino)phenylacetyl]oxy]milbemycinB.

Most especially preferred are topical localized formulations, whereinthe composition comprises)4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(Compound A) and) moxidectin; or compound A; and selamectin, or CompoundA and milbemycin, or Compound A and eprinomectin.

The macrocyclic lactone compounds are well known to a person skilled inthe art and are easily obtained either commercially or throughtechniques known in the art.

The effective amount of the macrocyclic lactone compound is preferablybetween about 0.001 mg/kg bodyweight, preferentially about 0.005 to 10mg/kg. The proportions, by weight, of the isoxazoline compound offormula (I) and of the macrocyclic lactone compound are preferablybetween about 5/1 and about 1/0.0001.

Other biologically active compounds useful in the formulations of thepresent invention can be selected from Insect Growth Regulators (IGRs)such as e.g. fenoxycarb, lufenuron, diflubenzuron, novaluron,triflumuron, fluazuron, cyromazine, methoprene, pyriproxyfen etc.,thereby providing both initial and sustained control of parasites (atall stages of insect development, including eggs) on the animal subject,as well as within the environment of the animal subject.

Most especially preferred are topical localized formulations, whereinthe composition comprises Compound A; and diflubenzuron or Compound Aand methoprene, or Compound A; and pyriproxyfen, or Compound A andfenoxycarb, or Compound A; and fluazuron.

The effective amount of the IGR compound is preferably between about 0.1mg/kg bodyweight, preferably about 1 mg, and about 10 mg. Theproportions, by weight, of the isoxazoline compound of formula (I) andof the IGR compound are preferably between about 5/1 and about 0.000/1.

One aspect of the current invention is a method for permanentlycombating a parasite in an environment in which the animal is subjectedto strong parasitic pressure where the administration of the topicallocalized formulation at a frequency far below a daily administration.For example, it is preferable for the treatment according to theinvention to be carried out monthly, every 2 months, 3 months, 4 months,5 months or 6 months especially on dogs, cats or ruminants (e.g. cattleor sheep).

The time period between treatments depends upon factors such as theparasite(s) being treated, the degree of infestation, the type of mammalor bird and the environment where it resides. It is well within theskill level of the practitioner to determine a specific administrationperiod for a particular situation.

In some embodiments of this invention, the topical localized formulationof an isoxazoline of Formula (I) is administered to treat parasitoses ofan animal (or make a medicament to treat parasitoses of an animal). Theterm “parasitoses” includes pathologic conditions and diseasesassociated with or caused by one or more ectoparasites directly, suchas, for example, anemia and flea allergy dermatitis. It also includespathologic conditions or diseases associated with caused by one or morevector-transmitted pathogens, such as, for example, Lyme disease,Ehrlichiosis (particularly Canine Ehrlichiosis), and Rocky Mountainspotted fever from vector ticks. The phrase “treatment of parasitoses”means to partially or completely inhibit the development of parasitosesof an animal susceptible to parasitoses, reduce or completely eliminatethe symptoms of parasitoses of an animal having parasitoses, and/orpartially or completely cure parasitoses of an animal havingparasitoses. In general, the treatment of parasitoses is achieved byadministering the formulation according to the invention comprising anisoxazoline of Formula (I) to control an ectoparasite infestation.

This invention also relates to treatment methods wherein at least anancillary goal of controlling ectoparasites in and/or on an animal is tocontrol an ectoparasitic infestation in an environment that is occupied(periodically or continuously) by the animal. In some such embodiments,for example, the animal is a companion animal (e.g., a cat or dog). Theenvironment may be, for example, a house or other shelter; a room; apen, a stall, or other confinement means; bedding; etc.

The topical localized formulations of the present invention areespecially suitable for combating parasites that infest mammals(including humans). Mammalian subjects include primates (e.g., monkeys),bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine(e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs),feline (e.g., house cats), camels, deer, donkeys, buffaloes, antelopes,rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils,and hamsters). Of particular note is the embodiment wherein the animalsto be protected are domesticated dogs (i.e. Canis lupus familiaris) anddomestic house cats (i.e. Felis catus).

Examples of invertebrate parasitic pests controlled by administering thetopical localized formulation of this invention to an animal to beprotected include ectoparasites (arthropods, acarines, etc) andendoparasites (helminths, e.g., nematodes, trematodes, cestodes,acanthocephalans, etc.).

In particular, the formulations of this invention are effective againstectoparasites including: flies such as Haematobia (Lyperosia) irritans(horn fly), Stomoxys calcitrans (stable fly), Simulium spp. (blackfly),Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Muscaautumnalis (face fly), Musca domestica (house fly), Morellia simplex(sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypodermalineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphoraspp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly),Culicoides spp. (midges), Hippobosca equine, Gastrophilus instestinalis,Gastrophilus haemorrhoidalis and Gastrophilus naslis; lice such asBovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicolasubrostratus, Heterodoxus spiniger, Lignonathus setosus and Trichodectescanis; keds such as Melophagus ovinus; mites such as Psoroptes spp.,Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp.,Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites);ticks such as Ixodes spp., Boophilus spp., Rhipicephalus spp., Amblyommaspp., Dermacentor spp., Hyalomma spp. and Haemaphysalis spp.; and fleassuch as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dogflea).

This invention also is directed to kits that are, for example, suitablefor use in performing the treatment methods described above. In general,such a kit will comprise a topical localized formulation according tothe invention comprising a therapeutically effective amount of aisoxazoline of Formula (I), and an additional component(s). Theadditional component(s) may be, for example, one or more of thefollowing: a diagnostic tool, instructions for administering thecomposition, an apparatus for administering the composition, a containercomprising an excipient or other active ingredient to be mixed oradministered in combination with the composition, or a memory aid (e.g.,a stamp to adhere to a calendar to remind an animal owner of a time toadminister a subsequent dose of the composition).

As used in the specification and claims, the terms “about” and“approximately” designate that a value is within a statisticallymeaningful range. Such a range can be typically within 20%, moretypically still within 10%, and even more typically within 5% of a givenvalue or range. The allowable variation encompassed by the terms “about”and “approximately” depends on the particular system under study, andcan be readily appreciated by one of ordinary skill in the art.

As used herein, the term “w/w” designates weight/weight, the term “w/v”designates weight/volume, and the term “mg/kg” designates milligrams perkilogram of body weight.

Example 1

Preparation of Formulations According to the Invention:

Composition C

The calculated amount of e.g. 7 grams of4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(Compound A), were weighted and filled into a flask. The required volumeof excipients was added, e.g. 8 mL of DMA and 6.25 mL of DMSO. CompoundA was dissolved under mild stirring or shaking. This solution wasbrought to a final volume of 25 mL with ethyl lactate.

Using essentially the same procedure described hereinabove forcomposition C, composition A-V of table 2 and the formulations of table3 were prepared. An alternative approach to the preparation was toweigh-in the excipients. The required weight was calculated based on thedensity of each product. Or, the order of addition was changed, e.g.excipients were blended and Compound A was introduced at a later stage.

Physicochemical parameters, that indicate the suitability of theformulations for topical localized (e.g. spot-on) administration, wereevaluated. Compositions A to V of table 2 were tested using thefollowing procedures

Viscosity: The newtonian viscosity (η) was determined by means of arotational viscometer in a double gap cup and rotor system at 20° C.

Evaporation: The evaporation was determined in a weight-recordingbalance. The sample pan was heated to 50° C. over 4 h and weight losswas recorded.

Spreading diameter: The spreading diameter was determined by measuringthe diameter of three 20 μL spots of test product on a sheet of plastic.

Water absorption: The water absorption was determined by determining thewater concentration of a test product in contact with the surroundingatmosphere at a temperature of 25° C. after one day. In addition, thephysical state of the test product, e.g. whether it was a clearsolution, was also recorded.

Solubility: A saturated solution, i.e. a solution of a test compound incontact with undissolved particles of the test compound, was preparedand continuously shaken, temperature was recorded. The content of thecompound in the solvent phase was determined by HPLC after approximately24 h. The content result was taken as solubility. In some cases, thecontent was determined again after 48 h and the lower of the two resultswas taken as solubility.

Compatibility: Binary mixtures of the test compound and excipients wereprepared and stored under defined storage conditions, e.g. 40° C., 75%RH. At study start and after defined storage periods, samples wereanalyzed for appearance, content and degradation products.

The physicochemical parameters of the formulations of Table 2 aresummarized in Table 2a. The results in Table 2a and the in vivoexperiments where the formulations were administered to dogs show thatthe tested formulations are suitable for localized topicaladministration of isoxazoline compounds to animals.

Comparative Example 2

Spot-on formulations with conventional topical localized formulationsand isoxazoline compound solvents that were suggested e.g. in WO2009/024541 were prepared and the solubility was tested in vitro asindicator for their suitability as formulations for localized topicaladministration of isoxazoline compounds to animals.

The details of the tested formulations are outlined in Table 4a(Comparative examples (1-7).

Compound A was not soluble in compare formulations 1, 2 and 3 at roomtemperature and 5° C.

Crystals/precipitations were detected in compare formulations 4 and 5aafter leaving the formulations for some time exposed to the surroundingatmosphere.

Example 3

In Vivo Trials—Spot-on Administration of the Formulations to Dogs

The formulations of Table 2 were administered as spot-on to dogs at an4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(Compound A) dosis of 25 mg/kg bodyweight. Dogs were observed for localand systemic tolerance of the treatment and the cosmetic appearance ofthe administration site was evaluated.

Plasma samples were taken of all dogs pre-administration and 2, 4, 8hours after administration, on Day, D1, D3, D7 and, D14 and subsequentlyweekly until D56. The plasma was analyzed for Compound A by HPLC-MS/MS.

Results: The mean concentration of compound A in dog plasma is shown inFIGS. 1 to 6.

No local or systemic adverse reactions were observed. The cosmeticappearance was acceptable for the formulations, as only minor effects onappearance were detected for a short duration.

Example 4

In Vivo Trials—Formulation Comprising Compound a and Moxidectin Spot-onAdministration to Dogs

Formulation N of Table 2 was administered as spot-on to dogs at aCompound A dosage of 25 mg/kg bodyweight and moxidectin dosage of 2.5mg/kg bodyweight. Dogs were observed for local and systemic tolerance ofthe treatment and the cosmetic appearance of the administration site wasevaluated. Plasma samples were taken of all dogs pre-administration 2,4, 8 hours after administration, on Day 0, D1, D3, D7 and D14 andsubsequently weekly until 10 D56. The plasma was analyzed for Compound Aand moxidectin concentration.

Results: The mean plasma concentration of the compound A and moxidectinin dogs is shown in FIG. 7.

No local or systemic adverse reactions were observed. The cosmeticappearance was acceptable.

Example 5

Evaluation of the Efficacy of Test Formulations Against Ticks in Dogs

In this evaluation, Beagle dogs of mixed sex, were used and assigned totreatment and control groups. On day D −2, each dog was infested with 50unfed adult ticks, Rhipicephalus sanguineus (R. sanguineus).

The dogs received on Day 0 the treatments (formulations indicated intable 1) at a dosage of 25 mg/kg body weight of the Compound A. Theformulations were administered using a pipette.

The dose was applied as a line at the dorsal neck at the base of theskull.

One Group was left untreated. The dogs were observed for any immediatereactions to the treatments, and were observed for post-treatmentadverse reactions, skin irritation, and behavior of test formulations atthe time of treatment, after approximately 2, 4 and 8 hours, and on Days1, 2 and 7 following administration of the treatments. Thereafter, dogswere observed once daily for the remainder of the study.

All ticks were removed 48 hours after treatment. Removed ticks wereassessed according to the following categories: Efficacy No: for—livefree, live attached—live engorged/not engorged, and dead—engorged,Efficacy Yes: For dead, free, dead attached not engorged.

Tick counts were transformed and geometric means were used to calculatepercent efficacy for the treatments. The results are shown in Table 1.

TABLE 1 Result of in vivo efficacy studies Tick efficacy Formulationafter 2 days No. Study characteristics [geometric mean, %] C R.sanguineus, 6 dogs, 88.5-94.5 notional control groups H R. sanguineus, 6dogs, 91.8-96.1 notional control groups J R. sanguineus, 4 dogs,81.6-91.1 notional control groups L R. sanguineus, 4 dogs, 45.7-73.9notional control groups M R. sanguineus, 4 dogs, 98.4-99.2 notionalcontrol groups N R. sanguineus, 4 dogs, 96.5-98.3 notional controlgroups R R. sanguineus, 4 dogs, 98.4-99.2 notional control groups

Example 6

Assessment for Cosmetic Effects after Topical Administration in aVariety of Dog Breeds and Coat Lengths and Characteristics

Test Formulations C and H of Table 2 were Evaluated.

The study was conducted using 40 mixed sex adult dogs (n=20 performulation) with a range of body weights and ages. The formulation wasadministered as a topical line-on directly to the skin between theshoulder blades and the lumbosacral region. The length of the line wasdetermined by the dosing volume.

The application site and the hair coat was observed closely forspreading of the formulations and for determining if any of the spot-onsolution ran off the animal during and directly after administration.Furthermore the application site was observed for signs of residues andwetness at 8, 24, 48 and 96 hours after administration. In addition toobservations of the application site appearance, the overall appearanceof the dogs' coat was assessed, particularly the hair in the proximityof the administration site for signs such as dryness, wiry look,brittleness, dullness, hair loss and the appearance of residue and thesmell of hair and skin.

The skin was assessed for signs of local irritation. Furthermore dogswere observed for systemic tolerance

For each time point each assessment parameter was scored (compared tothe pre-administration score on D0) as 0=no change, 1=slight change,2=moderate change or 3=severe change.

Results: The scoring is summarized in Tables A to D.

The formulations were easy to apply and did not emanate any noticeableodor. The drying time after application was fast for both formulationsFormulation C displayed a propensity to form some powdery residues inthe hair of 10 dogs at 8 hour assessment. As for the overall appearanceat 24 hours, the application site was not noticeable on 17 dogs forFormulation C and on 15 dogs for Formulation H.

TABLE A Group 1 Formulation C Wetness post application Number of dogswith each score reduced Time post 1 (slightly application 3 (wet) 2(greasy) greasy) 0 (dry  8 hours 0 3 4 13 24 hours 0 0 0. 20 48 hours 00 0 20 96 hours 0 0 0 20

TABLE B Group 1 Formulation C Residues post application Number of dogswith each score reduced Time post 0 (no application 3 (severe) 2(moderate) 1 (slight change)  8 hours 4 1 5 10 24 hours 2 5 3 10 48hours 0 7 2 11 96 hours 1 4 5 10

TABLE C Group 2 Formulation H Wetness post application Number of dogswith each score reduced Time post 1 (slightly application 3 (wet) 2(greasy) greasy) 0 (dry  8 hours 0 2 8 10 24 hours 0 0 2 18 48 hours 0 00 20 96 hours 0 0 0 20

TABLE D Group 2 Formulation H Residues post application Number of dogswith each score reduced Time post 0 (no application 3 (severe) 2(moderate) 1 (slight change)  8 hours 0 0 0 20 24 hours 0 3 2 15 48hours 0 1 4 15 96 hours 0 1 3 16

Example 7

Assessment for Cosmetic Effects after Topical Administration in aVariety of Dog Breeds and Coat Lengths and Characteristics

Formulation N of Table 2 was evaluated.

The study was conducted using 38 mixed sex adult dogs with a range ofbody weights and ages. The formulation was administered as a topicalline-on directly to the skin between the shoulder blades and thelumbosacral region. The length of the line was determined by the dosingvolume.

The application site and the hair coat was observed closely forspreading of the formulations and for determining if any of the spot-onsolution ran off the animal during and directly after administration.Furthermore the application site was observed for signs of residues andwetness at 8, 24, 48 and 96 hours after administration. In addition toobservations of the application site appearance, the overall appearanceof the dogs' coat was assessed, particularly the hair in the proximityof the administration site for signs such as dryness, wiry look,brittleness, dullness, hair loss and the appearance of residue and thesmell of hair and skin.

The skin was assessed for signs of local irritation. Furthermore dogswere observed for systemic tolerance

For each time point each assessment parameter was scored (compared tothe pre-administration score on D0) as 0=no change, 1=slight change,2=moderate change or 3=severe change.

Results: Summarized scoring is shown in Table E and F.

The formulation N was easy to apply and did not emanate any noticeableodor. The drying time after application was fast. As for the overallappearance at 24 hours, the application site was visible on 13 dogs butnot noticeable on the remaining 25 dogs.

TABLE E Wetness post application Number of dogs with each score reducedTime post 1 (slightly application 3 (wet) 2 (greasy) greasy) 0 (dry  8hours 2 11 12 13 24 hours 0 4 8 26 48 hours 0 1 4 33 96 hours 0 0 1 37

TABLE F Residues post application Number of dogs with each score reducedTime post 0 (no application 3 (severe) 2 (moderate) 1 (slight change)  8hours 0 0 0 38 24 hours 0 0 2 36 48 hours 0 2 5 31 96 hours 0 1 2 35

Comparative Example 8

Spot-on formulations with conventional topical localized formulationsand isoxazoline compound solvents that were suggested e.g. inWO2009/024541 were prepared. Such formulations were administered asspot-on to dogs to evaluate their cosmetic appearance after localizedtopical administration to animals.

The details of the tested formulations are outlined in Table 4b.

Crystals/precipitations were detected after administration of compareformulations 5b, 6 and 7 after some hours on the majority of the dogsunder assessment. Other observations regarding the cosmetic appearancewere a certain stickiness of the hair coat at the administration siteand a noticeable wetness in a smaller portion of the dogs.

TABLE 2 Formulations of Compound A, Excipient: Amount [ml or mg] MethylEthyl ethyl Formulation active DEET Acetone DMSO DMA Lactate EthanolEucalyptol Glycofurol ketone Povidone No. (mg) (mL) (mL) (mL) (mL) (mL)(mL) (mL) (mL) (mL) (mg) A 280 0.11 0.41 0.36 0.20 B 250 0.18 0.15 0.50C 280 0.15 0.25 0.32 0.09 D 250 0.23 0.10 0.35 0.15 E 280 0.14 0.14 0.360.17 F 250 0.10 0.20 0.25 0.18 0.05 20 G 250 0.23 0.40 0.20 H 280 0.100.35 0.16 0.20 I 250 0.17 0.15 0.10 0.4 J 250 0.15 0.07 0.25 0.35 K 2800.17 0.14 0.35 0.15 L 400 0.15 0.27 0.30 M 333 0.20 0.17 0.40 N 250 0.100.18 0.35 0.20 O 250 0.18 0.25 0.40 P 280 0.10 0.16 0.35 0.20 Q 300 0.440.35 R 250 0.18 0.10 0.25 0.30 S 280 0.14 0.10 0.36 0.04 0.17 T 250 0.150.25 0.35 0.07 U 250 0.18 0.30 0.25 0.10 V 250 0.10 0.22 0.5

TABLE 2a Physicochemical parameters of formulations Water Viscos-Spread- absorption Formula- Solubility ity Evapora- ing after 1 d tionNo. [mg/mL] [mPas] tion [%] [mm] [appearance, %] A 9.44 35.05 B 679.33.69 47.81 24.13 Clear, 25.74 C 719.4 7.64 34.46 21.06 Clear, 40.27 D623.2 4.41 42.16 26.44 Clear, 48.44 E 8.63 34.91 F 754.7 19.86 39.3314.50 Turbid, 41.35 G 658.9 3.79 44.12 23.81 Clear, 41.33 H 601.7 13.5136.26 22.21 Clear, 34.73 I 728.3 3.65 47.03 28.1 Clear, 38.16 J 767.274.96 42.39 13.11 Clear, 45.35 K 6.82 34.72 L 627.8 7.25 38.05 18.52Clear, 42.55 M 602.1 5.35 38.28 23.68 Clear, 50.36 N 611.5 5.72 35.5818.88 Clear, 39.22 O 499.1 8.17 40.36 31.47 Turbid, 51.67 P 617.2 5.7935.72 19.76 Clear, 29.84 Q 32.92 20.11 11.63 Not determined, 32.81 R685.6 5.41 37.26 11.26 Clear, 47.34 S 8.09 32.82 T 706.10 6.48 38.7916.80 Clear, 43.28 U 637.8 4.10 40.24 16.75 Clear, 48.48 V 721.7 2.6056.12 33.1 Clear, 38.81

TABLE 3 Formulations of Compound A, Excipient: Amount [ml or mg] (utv =until total volume) Diethylene Methyl glycol Ethyl L- ethyl activeAcetone DMA DMSO Glycofurol Cyclohexanone onoethyl NMP Dimethyl lactateketone Eucalyptol [mg] DEET [mL] [mL] [mL] [mL] [mL] ether [mL] [mL]isosorbide [mL] [mL] [mL] 250 0.15 utv 0.05 0.1 0.1 250 0.1 utv 0.25 0.10.1 250 0.1 utv 0.1 0.05 0.2 250 0.1 utv 0.2 0.05 250 0.1 0.1 0.05 utv250 0.15 utv 0.15 0.05 250 utv 0.35 0.2 0.05 300 utv 0.3 0.2 0.2 250 utv0.25 0.25 0.05 250 utv 0.25 0.3 250 utv 0.3  0.25 300 utv 0.25 0.35 2500.15 utv 0.05 0.05 0.2 250 0.15 0.3 0.05 utv 250 0.2 utv 0.05 250 0.20.05 utv 250 0.15 utv 0.1 0.1 250 0.15 utv 0.05 0.1 0.15 250 utv 0.2 0.10.3 250 utv 0.3 0.1 0.2 300 utv 0.25 0.35 280 0.14 utv 0.36 0.17 0.04active Acetone DMA DMSO Glycofurol Ethyl L-lactate Methyl ethylEucalyptol [mg] DEET [mL] [mL] [mL] [mL] [mL] ketone [mL] [mL] 250 0.2utv 0.1 0.1 0.1 250 0.2 utv 0.1 0.1 250 0.2 utv 0.05 0.1 250 0.17 utv0.05 0.1 250 utv 0.35 0.1 0.15 250 utv 0.35 0.1 0.15 250 0.2 utv 0.1 0.2250 0.15 utv 0.25 0.2 250 0.15 utv 0.25 0.25 250 0.2 utv 0.1 0.3 250 0.20.4  utv 250 0.2 0.3  utv 250 0.15 0.35 0.25 utv 280 0.1 0.35 0.2 utv280 0.1 0.12 0.35 0.2 utv 280 0.1 0.08 0.35 0.2 utv 280 0.1 0.04 0.350.2 utv 280 0.15 0.35 0.22 utv 280 0.15 0.32 0.25 utv active Acetone DMADMSO MEK Eucalyptol gamma Isopropyl L Menthol Limonene [mg] DEET [mL][mL] [mL] [mL] [mL] Hexalactone [mL] alcohol [mL] [mg] [mL] 250 utv 0.350.25 0.05 250 0.1  0.2 utv 0.25 0.05 250 utv 0.2 0.25 0.1 250 utv 0.30.25 0.1 0.15 250 utv 0.3 0.2 0.2 250 utv 0.25 0.2 0.2 300 utv 0.35 0.3250 utv 0.25 100 333 0.17 utv 0.32 100 400 0.17 utv 0.25 100 250 0.17utv 0.4 utv 250 0.15 0.3 utv 250 0.2  0.3 utv 400 0.15 0.3 utv 250 0.150.35 300 utv 0.35 0.2 250 utv 0.4 0.2 250 0.15 utv 0.2 250 utv 0.25 0.3300 utv 0.35 0.25 active Acetone DMA DMSO Methyl ethyl EucalyptolPovidone gamma [mg] DEET [mL] [mL] [mL] ketone [mL] [mL] K90 [mg]Nonalactone [mL] 250 0.2 utv 0.1 0.2 250 utv 0.35 0.3 250 0.1 0.2  utv0.25 0.05 20 250 utv 0.35 0.25 50 250 utv 0.35 0.25 10 250 utv 0.35 0.2515 250 utv 0.35 0.25 250 utv 0.35 0.25 250 0.1 utv 0.1 250 0.2 utv 0.4250 0.2 utv 0.25 250  0.15 utv 0.35 300 utv 0.1  0.35 300 utv 0.1  0.5250 utv 0.15 0.5 250 0.1 utv 0.5 250 utv 0.15 0.4 0.1 active Acetone DMADMSO Glycofurol Propylene glycol Povidone Polybutene Poloxamer Nerol[mg] DEET [mL] [mL] [mL] [mL] methyl ether [mL] K17 [mg] [mg] 124 [mL][mL] 250 utv 0.1 0.5 0.05 250 utv  0.35 0.25 0.05 250 0.2 utv 0.4 10 250utv  0.35 0.25 50 250 0.2 utv 0.4 300 0.2 utv 0.4 300 0.2 utv 0.3 3000.17 utv 0.3 250 0.15 utv 0.35 0.25 300 utv 0.2 0.35 300 utv 0.2 0.35250 utv 0.5 0.1 250 utv 0.25 0.3 250 utv 0.25 0.4 250 utv 0.3 0.2 2500.05 utv 0.4 0.2 250 0.1 utv 0.35 0.2 250 0.15 utv 0.25 0.35 250 0.18utv 0.2 0.35 250 0.18 utv 0.25 0.3 250 0.18 utv 0.3 0.25 400 0.15 utv0.44 400 0.15 utv 0.3 333 0.2 utv 0.4 280 0.1 utv 0.35 0.2 280 0.15 utv0.42 0.1 280 0.17 utv 0.35 0.15 280 0.07 utv 0.4 0.2 280 0.15 utv 0.320.2 280 0.09 utv 0.38 0.2 280 0.11 utv 0.36 0.2 280 0.14 utv 0.36 0.1710 0.17 utv 0.45 0.21 250 0.1 utv 0.35 0.2 300 utv 0.35 280 0.1 utv 0.350.2

TABLE 4 a Comparative examples in vitro tested Dipropylene glycol EthylPropylene Isopropyl Benzyl- Formulation active DEET NMP DMSO monomethylLactate glycol myristiate alcohol No. (mg) (mL) (mL) (mL) ether (mL)(mL) (mL) (mL) (mL) Compare 1 500 0.45 utv 0.10 Compare 2 500 — 0.35 utv0.1 Compare 3 500 — 0.3 utv Compare 4 500 — 0.35 utv 0.075 Compare 5a500 0.45 utv

TABLE 4 b Comparative examples in vivo tested Dipropylene Phenyl- glycolBenzyl- ethyl- Formulation active DEET NMP DMSO monomethyl alcoholalcohol No. (mg) (mL) (mL) (mL) ether (mL) (mL) (mL) Compare 5b 500 —utv Compare 6 500 — 0.35 utv Compare 7 500 — utv

What is claimed is:
 1. A topical localized formulation for the treatmentor prophylaxis of parasite infestation in animals which comprises aneffective amount of4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamideand a veterinary acceptable liquid carrier vehicle wherein the liquidcarrier vehicle comprises N,N-diethyl-3-methylbenzamide as a solvent. 2.The topical localized formulation according to claim 1, wherein theformulation comprises 1 to 50% N,N-diethyl-3-methylbenzamide.
 3. Thetopical localized formulation according to claim 1, wherein the liquidcarrier vehicle comprises N,N-diethyl-3-methylbenzamide as solvent and aco-solvent selected from the group consisting of dimethyl sulfoxide,acetone, dimethylacetamide, ethyl alcohol, eucalyptol, dipropyleneglycol monomethyl ether, methylethyl ketone, glycofurol,ethyl-L-lactate, and a mixture of at least two of these co-solvents. 4.The topical localized formulation according to claim 1 wherein theliquid carrier vehicle comprises N,N-diethyl-3-methylbenzamide assolvent and a mixture of at least two of acetone, ethyl-L-lactate,dimethyl sulfoxide, dimethylacetamide and glycofurol.
 5. The topicallocalized formulation according to claim 1 wherein there is aweight/weight ratio of the cosolvent/solvent in the spot-on compositionand the weight/weight ratio of the cosolvent/solvent is between 4/1 and1/5.
 6. The topical localized formulation according to claim 1, whereinthe formulation further comprises an effective amount of one or morecompounds selected from a macrocyclic lactone compound or an insectgrowth regulator compound.
 7. The topical localized formulation of claim6, wherein the macrocyclic lactone compound is selected from ivermectin,moxidectin, milbemycin, selamectin, emamectin, latidectin and lepimectinor a salt thereof and the insect growth regulator compound is selectedfrom fenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron,fluazuron, cyromazine, methoprene and pyriproxyfen.
 8. The topicallocalized formulation of claim 1, wherein the liquid carrier vehiclecomprises N,N-diethyl-3-methylbenzamide as solvent and a co-solventselected from the group consisting of dimethyl sulfoxide, acetone,dimethylacetamide, ethyl alcohol, eucalyptol, dipropylene glycolmonomethyl ether, methylethyl ketone, glycofurol, ethyl-L-lactate, and amixture of at least two of these co-solvents.
 9. The topical localizedformulation of claim 1, wherein the formulation comprises4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide,N,N-diethyl-3-methylbenzamide, dimethyacetamide, acetone and glycofurol.10. The topical localized formulation of claim 9, further comprisingmoxidectin.